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  • Tuberculosis

    Jed Gorden MDUniversity of Washington

    Vietnam Lecture Series 2001

  • Tuberculosis

    Mycobacterium Tuberculosis (TB) = #1 Cause of Death Worldwide from a Single Infectious Agent

    1993 World Health Organization: Declared TB Global Health Emergency

  • TB: History

    Earliest Archeological Evidence of Spinal TB is from Egyptian Mummies, 4000 BCE.

    Earliest Evidence of Pulmonary TB 1000 BCE in a 5 Year old Boy

  • TB: History

    Earliest Written Description 668-626 BCE:

    The Patient Coughs Frequently, His sputum is Thick and Sometimes Contains Blood. His Breathing is Like a Flute, His Skin is Cold but His Feet are Hot. He Sweats Greatly

    and his Heart is Much Disturbed.

  • TB: Ancient Names

    Hindus = Sosha = CoughRayakshma = Waisting

    Greeks = Phtisis = To Waste

    English Term From Latin = Consumption

  • TB: History

    TB Peak = Industrial Revolution 17th- 18th CenturyResulting in 25-30% of all Adult Deaths in Europe

  • TB: Epidemiology

    Estimates for 1990 World Wide # Infected = 1.7 Billion World Wide # Deaths = 3 Million SE Asia # Infected = 426 Million SE Asia # New Cases = 2.47 Million SE Asia # Deaths = 900 Thousand

  • TB: Transmition

    Infection = Person to Person via Airborne Infectious Aerosol:

    CoughingSneezingTalking

  • Transmission and Pathogenesis

  • TB: Transmition

    Aerosolized Droplets 5 Micrometers = 1-400 Bacilli

    Estimated 5-200 Organisms Required for Infection

  • TB: Transmition

    Influences on Becoming Infected:Infected Contact

    Duration of Exposure*Ventilation in Infected Environment

    *Suspended Airborne Particles are Infectious after Source Leaves the Room

  • TB: Natural History

    Inhaled Particle*

    Dissemination*

    Immune System Activation*

    Granuloma Formation

  • CXR with evidence of TB infection

  • TB: Disease

    Estimated Only 10% of Immunocompitent People Infected With TB (PPD+) Will Develop Clinically Significant Disease

    50% in First 2-3 years Following Exposure 50% in Remote Future

  • TB: Disease

    Estimated Only 10% of Immunocompitent People Infected With TB (PPD+) Will Develop Clinically Significant Disease

    50% in First 2-3 years Following Exposure 50% in Remote Future

  • TB: Determinants of Disease Defects in Cell Mediated Immunity

    Advanced AgeMalnutrition

    Genetic FactorsImmunosuppressive Meds

    Co-existing Disease: DiabetesMalignancyHIVRenal Failure

  • TB: Disease Pattern

    Primary Tuberculosis

    Reactivation Tuberculosis

  • TB: Primary

    Associated With New TB Exposure Symptoms in Series of 517 New Converters:

    Fever 70% (Duration 2-10 Weeks)Chest Pain 25%

    Pleuritic Chest PainErethema Nodusum Lower Extremities

    (Women > Men)

  • TB: Primary Chest X-Ray

    Hilar Adenopathy 64% (Children > Adults) Hilar Changes Right > Left Pleural Effusion 29% (Adults > Children) Unilateral Infiltrate/Ipsolateral Hilar Nodes 27%

  • Possible primary tuberculous pneumonia

  • TB: Reactivation

    Accounts For 90% of Adult non HIV TB

    Reactivation = Result of a Previously Dormant Organism Implanted Years Before by a Primary Infection

    Most Common Location = Apical Post Segment of Lung

  • TB Reactivation: Symptoms

    Nonspecific Cough 78%

    Weight Loss 74% Fatigue 68%

    Temperature 60% Night Sweats 55% Hemoptosis 37%

  • TB Reactivation: Physical Exam

    Non Specific

  • Apical Cavitary Disease

  • TB: Diagnosis

    PPD Sputum Examination

    Chest X-Ray Culture

  • TB: PPD

    PPD = Purified Protein Derivative

    The Tuberculin Skin Test Identifies Individuals Who Have Been Infected With Mycobacterium Tuberculosis, it Does not Differentiate Between Old and New Infection

  • TB: PPD

    Dose of Tuberculin = 5TU

    Injection Site = Intradermally Dorsal Side of Forearm

    Inflammatory Reaction = 24-72 Hours

    Result Test in 48-72 Hours (If Positive at 6 Days = true Positive)

  • Testing for TB Disease and Infection

  • TB: PPD Resulting

    Diameter of Induration = Determinant of Disease

    Technique: Use Ball Point Pen Start 1-2 cm Away from Margin of Test When Ball Point Pen Reaches the Margin Resistance is Felt. Repeat From Opposite Side. Distance between Lines = Diameter

  • Reading the Tuberculin Skin Test

    Read reaction 48-72 hours after injection

    Measure only induration

    Record reaction in millimeters Correct Measurement

  • PPD Guidelines for Interpretation Size of Induration

    < 5mm

    > 5mm

    > 10mm

    > 15mm

    Considered Positive

    Never = +

    HIV+Close Contact of TB+

    + Chest X-Ray

    IV Drugs/HIV-At Risk Disease

    High Risk GeographyAll Patients

  • TB Chemo prophylaxis

    Isoniazide Prophylaxis Given to Tuberculin Reactors Reduces the Risk of Active TB by 90%

  • TB Chemo prophylaxis

    Isoniazid 300mg Single Daily Dose 6-12 Months

    HIV+ Patients Isoniazid 300mg Daily 12 Months

    Alternative: Isoniazid 15 mg/kg Twice Weekly 6-12 Months

    *All Regiments Require Patient Compliance For Efficacy

  • Risk of Isoniazid

    Hepatitis = Major Toxic Effect of Isoniazid< 20 Years Old = 0% Risk

    20-34 Years Old = 0.3% Risk35-49Years Old = 1.2% Risk50-65 Years Old 2.3% Risk

    Risk Increased With Alcohol Consumption

  • Risk of Isoniazid

    Peripheral Neuropathy

    Highest Risk in Diabetes, Malnutrition, Alcoholism

    Peripheral Neuropathy Prevention Co-Administer Pyridoxine

  • Micobacterium Tuberculosis in Sputum

  • Principles of Tuberculosis Treatment

    Regimens Must Contain Multiple Drugs

    Drugs Must be Taken Regularly

    Treatment Must be Continued for Sufficient Time(Minimal Acceptable Duration of Treatment = 6 Months)

  • Principles of Tuberculosis Treatment

    Any Regimen is Irrelevant if Drugs Do Not Enter The Patients Body. Promoting and

    Monitoring Adherence to The Drug Regimen Are Essential For Treatment To be

    Successful

  • Principles of Tuberculosis Treatment

    The World health Organization Advocates Directly Observed Therapy

    (DOT)

  • Drugs in Current Use

    Isoniazid Rifampin

    Pyrazinamide Ethambutol

    Streptomycin

  • TB: Treatment Option 1Drug Dose (Max) Duration

    Isoniazid 5-10mg/kg/day (300mg) 6 Months

    Rifampin 10mg/kg/day (600mg) 6 Months

    Pyrazinamide 25mg/kg/day (2.5g) First 2 Months

    Ethambutol 25mg/kg/day First 2 Months

  • TB: Treatment Option 2Daily: Isoniazid+Rifampin+Pyrazinamide+EthambutolDuration: Week 1+2

    +2 Times/Week: Isoniazid+Rifampin+Pyrazinamide+

    EthhambutolDuration: Week 2-8

    +2 Times/Week: Isoniazid+RifampinDuration: Week 8-24*Total Duration of Therapy 24 Weeks*Direct Observed Therapy Required For Short Course

  • TB: Treatment Option 33 Times/Week For Total 6 Months:

    Isoniazid+

    Rifampin+

    Pyrazinamide+

    Ethambutol*Directly Observed Therapy Required Short Course

  • Adjusted Treatment Dose

    50mg/kg Max 2.5g50mg/kg Max 2.5gEthambutol

    50-70mg/kg Max 4g50-70mg/kg Max 4gPyrazinamide

    10mg/kg Max 600mg10mg/kg Max 600mgRifampin

    15mg/kg Max 900mg15mg/kg Max 900mgIsoniazid

    3X/Week2X/WeekDrug

  • Ethambutol Caution

    Ethambutol Should not Be Used if Unable to Monitor Visual Acuity, Including in Small Children

    Substitute with StreptomycinDaily Dose = 15mg/kg Max 1g/dose2x/Week Dose = 25-30mg/kg Max 1.5 g/dose3x/Week Dose = 25-30mg/kg Max 1.5 g/dose

  • Toxicities of TB Treatment

    All therapies have significant toxicity All drugs are associated with hepatitis and

    hypersensitivity reactions Unique toxicities

    INH: hepatic necrosis, peripheral neuropathy Rifampin: altered drug metabolism Pyrazinamide: hyperuricemia Ethambutol: optic neuritis Streptomycin: vestibular toxicity

  • Evaluation Response To Treatment

    Response To Anti TB Chemotherapy is Best Evaluated Through Sputum Examination

    Recommend Sputum Evaluation Every Month

    After 2 Months of Therapy 85% of Patients = Sputum negative

  • Treatment Failure

    Consider Drug Resistance To Medical regimen

    Consider Poor Patient Compliance With Medical Regimen

  • TB and HIV

    Complex synergy between HIV and TB Annual risk of progression to disease is 10%

    this is up to 100-fold higher than in HIV -

    TB is aggressive in HIV, more likely to disseminate

    TB may be AIDS-defining illness Treatment is the same, but often a longer course Interactions between HIV meds and anti-TB drugs

  • TB: BCG Vaccination

    Live Attenuated Vaccine Derived From M. Bovis

    WHO: Recommended For Young Children

    Vaccination = 60-80% Decrease in Disease Does Not Prevent Infection

    Effect of BCG on PPD Decreases With Time

  • Allocation of TB Resources

    Infection Case Finding and Treatment

    Contact Investigation and Treatment

  • TB: Summary

    Endemic Disease With Significant Mortality and Morbidity

    Resource Focus: Case Finding + Contact Treatment

    Treatment Requires Medication + Compliance

  • CASE: I A 56 Year Old Previously Healthy Woman

    Presents for Ca